SPCS3

Summary

SPCS3 (signal peptidase complex subunit 3, HGNC:26212) is a protein-coding gene on chromosome 4q34.2, encoding Signal peptidase complex subunit 3 (P61009). Essential component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum. It is a common-essential gene (DepMap: required in 95.1% of cancer cell lines).

Involved in obsolete signal peptide processing and viral protein processing. Located in endoplasmic reticulum membrane.

Source: NCBI Gene 60559 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 28 total — 1 pathogenic
• GTEx eGene: eQTL in 26 tissues, sQTL in 1 (q < 0.05)
• Cancer dependency (DepMap): dependent in 95.1% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.84 (intermediate), LOEUF 0.62 (unconstrained)
• MANE Select transcript: NM_021928

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26212
Approved symbol	SPCS3
Name	signal peptidase complex subunit 3
Location	4q34.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22649, SPC22/23, SPC3, YLR066W, PRO3567
Ensembl gene	ENSG00000129128
Ensembl biotype	protein_coding
OMIM	618854
Entrez	60559

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000503362

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 3

ENST00000503362, ENST00000507001, ENST00000507678, ENST00000513139, ENST00001044112, ENST00001121319, ENST00001121320, ENST00001133466

RefSeq mRNA: 1 — MANE Select: NM_021928 NM_021928

CCDS: CCDS54823

Canonical transcript exons

ENST00000503362 — 5 exons

Exon	Start	End
ENSE00000886396	176328198	176332245
ENSE00002065140	176319966	176320219
ENSE00003524373	176327162	176327277
ENSE00003530109	176322170	176322243
ENSE00003600295	176324181	176324257

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 65.8625 / max 367.3419, expressed in 1823 samples.

Highest expression (Bgee): corpus epididymis, gingival epithelium, pylorus, bone marrow cell, esophagus squamous epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SPCS3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 26 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 27 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	5.7e-12	+0.26	4:176328530:A:G
Cells Cultured fibroblasts	eqtl	1.5e-10	+0.19	4:176328605:A:G
Colon Sigmoid	eqtl	2.9e-08	-0.25	4:176305155:T:C
Muscle Skeletal	eqtl	4.3e-08	+0.21	4:176334636:TATATACACACAC:T
Testis	eqtl	4.9e-08	-0.29	4:176319985:C:T
Brain Nucleus accumbens basal ganglia	eqtl	5.8e-08	+0.28	4:176334975:G:A
Colon Transverse	eqtl	7.4e-07	-0.18	4:176307656:A:G
Esophagus Muscularis	eqtl	8.6e-07	+0.24	4:176334636:TATATACACACAC:T
Artery Aorta	eqtl	1.3e-06	+0.19	4:176328530:A:G
Cells EBV-transformed lymphocytes	eqtl	9.0e-05	+0.25	4:176335786:C:T
Esophagus Mucosa	eqtl	5.6e-04	+0.15	4:176328530:A:G
Brain Caudate basal ganglia	eqtl	8.5e-04	+0.21	4:176334975:G:A
Adipose Subcutaneous	eqtl	1.1e-03	+0.14	4:176334636:TATATACACACAC:T
Breast Mammary Tissue	eqtl	1.5e-03	+0.14	4:176317701:G:A
Adipose Visceral Omentum	eqtl	2.6e-03	+0.16	4:176328530:A:G
Artery Coronary	eqtl	3.3e-03	-0.51	4:176952700:T:G
Thyroid	eqtl	4.4e-03	+0.11	4:176335786:C:T
Esophagus Gastroesophageal Junction	eqtl	4.9e-03	+0.25	4:176334636:TATATACACACAC:T
Brain Spinal cord cervical c-1	eqtl	5.8e-03	-0.26	4:176228367:C:T
Lung	eqtl	7.6e-03	+0.15	4:176334636:TATATACACACAC:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
50700	65.3812	1823
50701	0.4813	215

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	97.62	gold quality
gingival epithelium	UBERON:0001949	97.61	gold quality
pylorus	UBERON:0001166	97.55	gold quality
bone marrow cell	CL:0002092	97.50	gold quality
esophagus squamous epithelium	UBERON:0006920	97.48	gold quality
decidua	UBERON:0002450	97.40	gold quality
body of pancreas	UBERON:0001150	97.37	gold quality
renal glomerulus	UBERON:0000074	97.15	gold quality
gingiva	UBERON:0001828	97.11	gold quality
germinal epithelium of ovary	UBERON:0001304	97.10	gold quality
monocyte	CL:0000576	96.95	gold quality
mononuclear cell	CL:0000842	96.95	gold quality
metanephric glomerulus	UBERON:0004736	96.94	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.87	gold quality
squamous epithelium	UBERON:0006914	96.83	gold quality
leukocyte	CL:0000738	96.81	gold quality
trabecular bone tissue	UBERON:0002483	96.72	gold quality
middle temporal gyrus	UBERON:0002771	96.69	gold quality
cardia of stomach	UBERON:0001162	96.61	gold quality
bone marrow	UBERON:0002371	96.61	gold quality
endometrium	UBERON:0001295	96.60	gold quality
parotid gland	UBERON:0001831	96.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.49	gold quality
caput epididymis	UBERON:0004358	96.48	gold quality
upper leg skin	UBERON:0004262	96.46	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.40	gold quality
seminal vesicle	UBERON:0000998	96.37	gold quality
trachea	UBERON:0003126	96.33	gold quality
buccal mucosa cell	CL:0002336	96.29	gold quality
tonsil	UBERON:0002372	96.26	gold quality
pancreas	UBERON:0001264	96.19	gold quality
epithelium of esophagus	UBERON:0001976	96.17	gold quality
heart right ventricle	UBERON:0002080	96.17	gold quality
endothelial cell	CL:0000115	96.14	gold quality
visceral pleura	UBERON:0002401	96.14	gold quality
nephron tubule	UBERON:0001231	96.12	gold quality
vermiform appendix	UBERON:0001154	96.08	gold quality
inferior olivary complex	UBERON:0002127	96.04	gold quality
caecum	UBERON:0001153	96.03	gold quality
superficial temporal artery	UBERON:0001614	96.03	gold quality
placenta	UBERON:0001987	95.99	gold quality
periodontal ligament	UBERON:0008266	95.97	gold quality
oviduct epithelium	UBERON:0004804	95.96	gold quality
substantia nigra pars compacta	UBERON:0001965	95.94	gold quality
lymph node	UBERON:0000029	95.88	gold quality
cauda epididymis	UBERON:0004360	95.88	gold quality
superior surface of tongue	UBERON:0007371	95.86	gold quality
pleura	UBERON:0000977	95.82	gold quality
lower lobe of lung	UBERON:0008949	95.79	gold quality
cranial nerve II	UBERON:0000941	95.64	gold quality
parietal pleura	UBERON:0002400	95.62	gold quality
palpebral conjunctiva	UBERON:0001812	95.55	gold quality
amniotic fluid	UBERON:0000173	95.42	gold quality
oral cavity	UBERON:0000167	95.41	gold quality
mammalian vulva	UBERON:0000997	95.39	gold quality
pericardium	UBERON:0002407	95.36	gold quality
epithelium of nasopharynx	UBERON:0001951	95.27	gold quality
stromal cell of endometrium	CL:0002255	95.22	gold quality
skin of hip	UBERON:0001554	95.20	gold quality
rectum	UBERON:0001052	95.03	gold quality
epithelial cell of pancreas	CL:0000083	94.96	gold quality
tongue squamous epithelium	UBERON:0006919	94.91	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.88	gold quality
penis	UBERON:0000989	94.85	gold quality
smooth muscle tissue	UBERON:0001135	94.84	gold quality
lung	UBERON:0002048	94.70	gold quality
islet of Langerhans	UBERON:0000006	94.67	gold quality
colonic mucosa	UBERON:0000317	94.67	gold quality
uterus	UBERON:0000995	94.67	gold quality
epithelium of mammary gland	UBERON:0003244	94.64	gold quality
blood vessel layer	UBERON:0004797	94.62	gold quality
mucosa of urinary bladder	UBERON:0001259	94.58	gold quality
trigeminal ganglion	UBERON:0001675	94.58	gold quality
tibia	UBERON:0000979	94.57	gold quality
nipple	UBERON:0002030	94.57	gold quality
saphenous vein	UBERON:0007318	94.57	gold quality
choroid plexus epithelium	UBERON:0003911	94.52	gold quality
urinary bladder	UBERON:0001255	94.49	gold quality
duodenum	UBERON:0002114	94.37	gold quality
tongue	UBERON:0001723	94.30	gold quality
jejunal mucosa	UBERON:0000399	94.28	gold quality
mammary duct	UBERON:0001765	94.24	gold quality
renal medulla	UBERON:0000362	94.20	gold quality
dorsal root ganglion	UBERON:0000044	94.18	gold quality
fallopian tube	UBERON:0003889	94.18	gold quality
mammary gland	UBERON:0001911	94.15	gold quality
thoracic mammary gland	UBERON:0005200	94.12	gold quality
kidney epithelium	UBERON:0004819	94.11	gold quality
adrenal tissue	UBERON:0018303	94.08	gold quality
right lung	UBERON:0002167	94.03	gold quality
nasal cavity mucosa	UBERON:0001826	94.00	gold quality
entorhinal cortex	UBERON:0002728	93.95	gold quality
metanephros	UBERON:0000081	93.89	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.80	gold quality
gall bladder	UBERON:0002110	93.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.70	gold quality
jejunum	UBERON:0002115	93.68	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.65	gold quality
layer of synovial tissue	UBERON:0007616	93.63	gold quality
upper lobe of lung	UBERON:0008948	93.63	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	105.24
E-MTAB-9467	yes	67.08
E-HCAD-1	yes	63.15
E-HCAD-4	yes	60.60
E-CURD-46	yes	54.14
E-CURD-122	yes	49.79
E-MTAB-8410	yes	39.63
E-HCAD-11	yes	23.09
E-HCAD-9	yes	19.59
E-MTAB-10553	yes	10.70
E-HCAD-13	yes	7.01
E-CURD-112	no	3.03
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Salivary gland	tissue	93.4	low
Bone marrow	tissue	64.3	low
Thyroid gland	tissue	58.2	medium
Appendix	tissue	47.8	medium
Pancreas	tissue	47.2	medium
Lymph node	tissue	47.1
Stomach 1	tissue	46.1	medium
Tonsil	tissue	45.2	low
Epididymis	tissue	44.8	medium
Cervix	tissue	43.8	medium
Spleen	tissue	43.8	not detected
Placenta	tissue	42.8	high
Liver	tissue	40.7	low
Urinary bladder	tissue	38.4	low
Endometrium 1	tissue	36.1	medium
Heart muscle	tissue	35.2	low
Rectum	tissue	35.2	medium
Colon	tissue	34.7	medium
Small intestine	tissue	34.7	high
Lung	tissue	34.1	medium
Breast	tissue	33.7	not detected
Thalamus	tissue	32.8
Choroid plexus	tissue	32.7
Smooth muscle	tissue	32.5	low
Duodenum	tissue	32.5	medium
Thymus	tissue	32.5
Superior colliculi	tissue	31.9
Kidney	tissue	31.8	medium
Adipose tissue	tissue	30.9	not detected
Prostate	tissue	30.8	low
Pons	tissue	30.2
Postcentral gyrus	tissue	30.2
Locus coeruleus	tissue	30.1
Gallbladder	tissue	30.0	medium
Nucleus accumbens	tissue	29.7
Parathyroid gland	tissue	29.4
Pituitary gland	tissue	28.5
Seminal vesicle	tissue	28.2	low
Midbrain	tissue	27.8
Hypothalamus	tissue	26.2
Hippocampus	tissue	26.1	low
Olfactory bulb	tissue	26.1
Cerebellum	tissue	25.9	not detected
Skin 1	tissue	25.4	low
Cerebral cortex	tissue	25.3	low
Substantia nigra	tissue	25.3
Somatosensory cortex	tissue	25.3
Hippocampal formation	tissue	25.1
Tongue	tissue	24.6
Vagina	tissue	24.1	not detected
Entorhinal cortex	tissue	23.9
Septum	tissue	23.9
Motor cortex	tissue	23.6
Esophagus	tissue	23.4	not detected
Adrenal gland	tissue	23.3	medium
Prefrontal cortex	tissue	23.2
Fallopian tube	tissue	23.2	medium
Occipital cortex	tissue	23.0
Temporal cortex	tissue	22.6
Cingulate cortex	tissue	22.5

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Ventral tegmental area (51.2), Lateral funiculus (white matter) (45.8), Dorsal funiculus (white matter) (42.8), Anterior funiculus (white matter) (41.5), Cervical spinal cord, ventral horn (39.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting SPCS3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 199 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-559	99.95	72.28	3609

Functional genomics

gnomAD constraint: pLI 0.838, LOEUF 0.623, missense Z 1.12 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000503362 — one region, missense o/e 0.64. DepMap (CRISPR cell-line fitness): dependent in 95.1% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): KMS-20 (-2.035), SNU-668 (-1.925), LOU-NH91 (-1.866), KALS-1 (-1.835), VCaP (-1.776), HCC1419 (-1.734), MHH-ES-1 (-1.714), PSN1 (-1.702), HCC1428 (-1.68), SNU-626 (-1.676), UACC-62 (-1.673), COR-L279 (-1.605), U-178 (-1.598), Calu-6 (-1.593), G-402 (-1.574).

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	spcs3	ENSDARG00000089976
mus_musculus	Arxes2	ENSMUSG00000048040
mus_musculus	Arxes1	ENSMUSG00000048355
rattus_norvegicus		ENSRNOG00000078288
drosophila_melanogaster	Spase22-23	FBGN0039172
caenorhabditis_elegans		WBGENE00019679

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Canis lupus familiaris	P61008	100.0%	Diamond
Bos taurus	Q3SZU5	100.0%	Diamond
Gallus gallus	P28687	90.0%	Diamond
Arabidopsis thaliana	Q53YF3	88.0%	Diamond
Caenorhabditis briggsae	Q60MW2	85.0%	Diamond
Saccharomyces cerevisiae S288C	Q12133	49.4%	Diamond
Debaryomyces hansenii CBS767	Q6BPD6	49.4%	Diamond
Yarrowia lipolytica CLIB122	Q6C4R5	47.0%	Diamond
Oryza sativa Japonica Group	Q9LGB4	46.8%	Diamond
Kluyveromyces lactis NRRL Y-1140	Q6CRY8	41.7%	Diamond
Dictyostelium discoideum	B0G180	40.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
HAFML	ncRNA	105377555
LINC02509	ncRNA	105377556
SPCS3-AS1	ncRNA	116435303
VEGFC	protein-coding	7424
SPATA4	protein-coding	132851
ASB5	protein-coding	140458
WDR17	protein-coding	116966

Protein

Protein identifiers

Signal peptidase complex subunit 3 — P61009 (reviewed: P61009)

Alternative names: Microsomal signal peptidase 22/23 kDa subunit

All UniProt accessions (1): P61009

UniProt curated annotations — full annotation on UniProt →

Function. Essential component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum. Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface. (Microbial infection) Plays an important role in virion production of flaviviruses such as West Nile virus, Japanese enchephalitis virus, Dengue virus type 2 and Yellow Fever virus.

Subunit / interactions. Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3. Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3. Within the complex, interacts with SEC11A or SEC11C and SPCS1. The complex induces a local thinning of the ER membrane which is used to measure the length of the signal peptide (SP) h-region of protein substrates. This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the SPCS3 family.

RefSeq proteins (1): NP_068747* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007653	SPC3	Family

Pfam: PF04573

UniProt features (6 total): topological domain 2, chain 1, transmembrane region 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
9RJB	Human Signal Peptidase in complex with artificial Signal Peptide L11	ELECTRON MICROSCOPY	2.6
9RJC	Apo Structure of the Human Signal Peptidase	ELECTRON MICROSCOPY	4.2
7P2P	Human Signal Peptidase Complex Paralog A (SPC-A)	ELECTRON MICROSCOPY	4.9
7P2Q	Human Signal Peptidase Complex Paralog C (SPC-C)	ELECTRON MICROSCOPY	4.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61009-F1	91.72	0.83

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	141

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 23; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

23 pathways:

ID	Pathway	Evidence
R-HSA-9918432	Maturation of DENV proteins ⚕	curated
R-HSA-9828806	Maturation of hRSV A proteins ⚕	curated
R-HSA-9768727	Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	curated
R-HSA-422085	Synthesis, secretion, and deacylation of Ghrelin	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway ⚕	—
R-HSA-9820965	Respiratory syncytial virus (RSV) genome replication, transcription and translation ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-418990	Adherens junctions interactions	—
R-HSA-446728	Cell junction organization	—
R-HSA-1500931	Cell-Cell communication	—
R-HSA-421270	Cell-cell junction organization	—
R-HSA-400508	Incretin synthesis, secretion, and inactivation	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-2980736	Peptide hormone metabolism	—
R-HSA-9764265	Regulation of CDH1 Expression and Function	—
R-HSA-9764274	Regulation of Expression and Function of Type I Classical Cadherins	—
R-HSA-9759476	Regulation of Homotypic Cell-Cell Adhesion	—
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane	electronic
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	electronic
R-HSA-400511	Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	electronic
R-HSA-72766	Translation	—

MSigDB gene sets: 184 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING, chr4q34, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_MATURATION, MORI_PLASMA_CELL_UP, WANG_RESPONSE_TO_FORSKOLIN_UP, IVANOVA_HEMATOPOIESIS_INTERMEDIATE_PROGENITOR, WANG_RESPONSE_TO_ANDROGEN_UP, WANG_PROSTATE_CANCER_ANDROGEN_INDEPENDENT, GOBP_SIGNAL_PEPTIDE_PROCESSING

GO Biological Process (4): proteolysis (GO:0006508), viral protein processing (GO:0019082), protein targeting to ER (GO:0045047), protein processing (GO:0016485)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), signal peptidase complex (GO:0005787), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

14 top-level categories:

Category	Pathways
Incretin synthesis, secretion, and inactivation	2
Peptide hormone metabolism	2
Metabolism of proteins	2
Translation	1
Regulation of CDH1 Expression and Function	1
Respiratory syncytial virus (RSV) genome replication, transcription and translation	1
Dengue Virus Genome Translation and Replication	1
Cell-cell junction organization	1
Cell junction organization	1
Cell-Cell communication	1
Disease	1
Adherens junctions interactions	1
Regulation of Expression and Function of Type I Classical Cadherins	1
Regulation of Homotypic Cell-Cell Adhesion	1

GO top-level categories

19 GO namespaces:

Category	Terms
protein metabolic process	1
viral process	1
viral gene expression	1
protein targeting	1
establishment of protein localization to endoplasmic reticulum	1
proteolysis	1
protein maturation	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
serine-type endopeptidase complex	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 10 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
proteolysis	BP	direct assay
viral protein processing	BP	mutant phenotype
endoplasmic reticulum	CC	direct assay
endoplasmic reticulum membrane	CC	direct assay

Protein interactions and networks

IntAct

Human interaction partners of SPCS3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
SEC11C	association	0.820	4
SEC11A	association	0.770	5
ATXN1	physical association	0.670	3
HTT	physical association	0.560	6
ENTPD6	association	0.530	2
UFD1	physical association	0.400	1
XRCC3	association	0.350	1

BioGRID (170 interactions; top human partners by supporting records): SEC11C (Affinity Capture-MS; 3 records), SPCS2 (Affinity Capture-MS; 3 records), CANX (Proximity Label-MS; 2 records), SEC11A (Affinity Capture-MS; 2 records), SLC22A14 (Cross-Linking-MS (XL-MS); 2 records), ABCB6 (Affinity Capture-MS), AMBRA1 (Proximity Label-MS), ANKRD46 (Affinity Capture-MS), AREL1 (Proximity Label-MS), ATXN1 (Affinity Capture-MS), C16orf58 (Affinity Capture-MS), C9orf72 (Affinity Capture-MS), CA9 (Proximity Label-MS), CALR3 (Proximity Label-MS), CDC123 (Affinity Capture-MS)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
SPCS3	“form complex”	“Signal peptidase complex, SEC11C variant”	binding
SPCS3	“form complex”	“Signal peptidase complex, SEC11A variant”	binding

Disease & clinical

Genetic variants

Variant evidence for SPCS3: 28 ClinVar records (1 pathogenic / likely pathogenic); 9 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

28 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	14
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
983279	GRCh37/hg19 4q32.3-35.1(chr4:169108358-184425536)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore SPCS3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 377):

Position(s)	Effect	Δscore	Sites
4:176320182	donor_gain	1.0000
4:176327232	donor_gain	1.0000
4:176327278–176327279	donor_loss	1.0000	6
4:176328302	donor_gain	1.0000
4:176328324	donor_gain	1.0000
4:176320220–176320221	donor_loss	0.9900	5
4:176327160–176327161	acceptor_loss	0.9900	6
4:176328196–176328197	acceptor_loss	0.9900	6
4:176320221	donor_loss	0.9800
4:176328195	acceptor_loss	0.9800

AlphaMissense

547 missense substitutions predicted likely pathogenic (of 1,171 scored), across 134 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D107	8	0.993	0.998
D131	8	0.983	0.993
D62	8	0.977	0.993
N81	8	0.977	0.998
F86	8	0.970	0.999
D53	8	0.920	0.982
D132	8	0.908	0.964
F129	8	0.883	0.991
F170	8	0.879	0.984
N149	8	0.869	0.990
W80	7	0.985	0.998
W106	7	0.982	0.998
F78	7	0.955	0.985
W148	7	0.951	0.998
F130	7	0.942	0.976
F54	7	0.936	0.985
D79	7	0.935	0.968
N101	7	0.927	0.992
F14	7	0.920	0.976
N9	7	0.909	0.992

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000575

Disease associations

OMIM: gene MIM:618854 | disease phenotypes:

GWAS associations

9 associations:

Study	Trait	p-value
GCST003989_18	Chin dimples	3e-15
GCST007354_11	Intracranial aneurysm	6e-13
GCST005989_11	Serum total protein levels	4e-9
GCST010796_3996	Electrocardiogram morphology (amplitude at temporal datapoints)	5e-9
GCST005988_4	Serum albumin levels	6e-9
GCST010796_3993	Electrocardiogram morphology (amplitude at temporal datapoints)	7e-9
GCST010796_3994	Electrocardiogram morphology (amplitude at temporal datapoints)	2e-8
GCST010796_3995	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-8
GCST004659_1	Left ventricular mass	1e-7

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0008205	left ventricular structural measurement
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066491 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	4
Valproic Acid	affects expression, increases expression	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Tunicamycin	increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cupric chloride	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
eprenetapopt	affects reaction, affects expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Benzo(a)pyrene	increases expression	1
Cisplatin	decreases expression	1
Colforsin	increases expression	1
Furaldehyde	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652513	Binding	Binding affinity to human SPCS3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2H5	Abcam HeLa SPCS3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for SPCS3 across ~30M SureChEMBL compounds — explore on Sugi Predict.